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Background: Accumulating evidence indicates that circular RNAs (circRNAs) play important roles in various cancers. Hsa_circ_0008832 (circFBXO7) is a circRNA generated from the second exon of the human F-box only protein 7 (FBXO7). Mouse circFbxo7 is a circRNA generated from the second exon of mouse F-box only protein 7 (Fbxo7). The role of human circFBXO7 and mouse circFbxo7 in non-small cell lung cancer (NSCLC) has not been reported. Methods: The expression of circFBXO7 was measured by quantitative real-time PCR. Survival analysis was performed to explore the association between the expression of circFBXO7 and the prognosis of patients with NSCLC. Lung cancer cell lines were transfected with plasmids. Cell proliferation, cell cycle, and tumorigenesis were evaluated to assess the effects of circFBXO7. Fluorescence in situ hybridization assay was used to identify the location of circFBXO7 and circFbxo7 in human and mouse lung cancer cells. Luciferase reporter assay was conducted to confirm the relationship between circFBXO7 and microRNA. Results: In this study, we found that circFBXO7 was downregulated in NSCLC tissues and cell lines. NSCLC patients with high circFBXO7 expression had prolonged overall survival. Overexpression of circFBXO7 inhibited cell proliferation both in vitro and in vivo. Mechanistically, we demonstrated that circFBXO7 upregulated the expression of miR-296-3p target gene Krüppel-like factor 15 (KLF15) and KLF15 transactivated the expression of CDKN1A. Conclusions: CircFBXO7 acts as a tumor suppressor by a novel circFBXO7/miR-296-3p/KLF15/CDKN1A axis, which may serve as a potential biomarker and therapeutic target for NSCLC.

Extracellular β-amyloid (Aβ) deposition and intraneuronal phosphorylated-tau (pTau) accumulation are the hallmark lesions of Alzheimer’s disease (AD). Recently, “sorfra” plaques, named for the extracellular deposition of sortilin c-terminal fragments, are reported as a new AD-related proteopathy, which develop in the human cerebrum resembling the spatiotemporal trajectory of tauopathy. Here, we identified intraneuronal sortilin aggregation as a change related to the development of granulovacuolar degeneration (GVD), tauopathy, and sorfra plaques in the human hippocampal formation. Intraneuronal sortilin aggregation occurred as cytoplasmic inclusions among the pyramidal neurons, co-labeled by antibodies to the extracellular domain and intracellular C-terminal of sortilin. They existed infrequently in the brains of adults, while their density as quantified in the subiculum/CA1 areas increased in the brains from elderly lacking Aβ/pTau, with pTau (i.e., primary age-related tauopathy, PART cases), and with Aβ/pTau (probably/definitive AD, pAD/AD cases) pathologies. In PART and pAD/AD cases, the intraneuronal sortilin aggregates colocalized partially with various GVD markers including casein kinase 1 delta (Ck1δ) and charged multivesicular body protein 2B (CHMP2B). Single-cell densitometry established an inverse correlation between sortilin immunoreactivity and that of Ck1δ, CHMP2B, p62, and pTau among pyramidal neurons. In pAD/AD cases, the sortilin aggregates were reduced in density as moving from the subiculum to CA subregions, wherein sorfra plaques became fewer and absent. Taken together, we consider intraneuronal sortilin aggregation an aging/stress-related change implicating protein sorting deficit, which can activate protein clearance responses including via enhanced phosphorylation and hydrolysis, thereby promoting GVD, sorfra, and Tau pathogenesis, and ultimately, neuronal destruction and death.

Adult hippocampal neurogenesis (AHN) is important for multiple cognitive functions. We sort to establish a minimal or non-invasive radiation approach to ablate AHN using guinea pigs as an animal model. 125I seeds with different radiation dosages (1.0, 0.8, 0.6, 0.3 mCi) were implanted unilaterally between the scalp and skull above the temporal lobe for 30 and 60 days, with the radiation effect on proliferating cells, immature neurons, and mature neurons in the hippocampal formation determined by assessment of immunolabeled (+) cells for Ki67, doublecortin (DCX), and neuron-specific nuclear antigen (NeuN), as well as Nissl stain cells. Spatially, the ablation effect of radiation occurred across the entire rostrocaudal and largely the dorsoventral dimensions of the hippocampus, evidenced by a loss of DCX+ cells in the subgranular zone (SGZ) of dentate gyrus (DG) in the ipsilateral relative to contralateral hemispheres in reference to the 125I seed implant. Quantitatively, Ki67+ and DCX+ cells at the SGZ in the dorsal hippocampus were reduced in all dosage groups at the two surviving time points, more significant in the ipsilateral than contralateral sides, relative to sham controls. NeuN+ neurons and Nissl-stained cells were reduced in the granule cell layer of DG and the stratum pyramidale of CA1 in the groups with 0.6-mCi radiation for 60 days and 1.0 mCi for 30 and 60 days. Minimal cranial trauma was observed in the groups with 0.3– 1.0-mCi radiation at 60 days. These results suggest that extracranial radiation with 125I seed implantation can be used to deplete HAN in a radioactivity-, duration-, and space-controllable manner, with a “non-invasive” stereotactic ablation achievable by using 125I seeds with relatively low radioactivity dosages.

Doublecortin (DCX) is transiently expressed in new-born neurons in the subventricular zone (SVZ) and subgranular zone (SGZ) related to adult neurogenesis in the olfactory bulb (OB) and hippocampal formation. DCX immunoreactive (DCX+) immature neurons also occur in the cerebral cortex primarily over layer II and the amygdala around the paralaminar nucleus (PLN) in various mammals, with interspecies differences pointing to phylogenic variation. The tree shrews (Tupaia belangeri) are phylogenetically closer to primates than to rodents. Little is known about DCX+ neurons in the brain of this species. In the present study, we characterized DCX immunoreactivity (IR) in the forebrain of Chinese tree shrews aged from 2 months- to 6 years-old (n = 18). DCX+ cells were present in the OB, SVZ, SGZ, the piriform cortex over layer II, and the amygdala around the PLN. The numerical densities of DCX+ neurons were reduced in all above neuroanatomical regions with age, particularly dramatic in the DG in the 5–6 years-old animals. Thus, DCX+ neurons are present in the two established neurogenic sites (SVZ and SGZ) in the Chinese tree shrew as seen in other mammals. DCX+ cortical neurons in this animal exhibit a topographic pattern comparable to that in mice and rats, while these immature neurons are also present in the amygdala, concentrating around the PLN as seen in primates and some nonprimate mammals.

Shank3 is a postsynaptic scaffolding protein of excitatory synapses. Mutations or variations of SHANK3 are associated with various psychiatric and neurological disorders. We set to determine its normal expression pattern in the human brain, and its change, if any, with age and Alzheimer’s disease (AD)-type β-amyloid (Aβ) and Tau pathogenesis. In general, Shank3 immunoreactivity (IR) exhibited largely a neuropil pattern with differential laminar/regional distribution across brain regions. In youth and adults, subsets of pyramidal/multipolar neurons in the cerebrum, striatum, and thalamus showed moderate IR, while some large-sized neurons in the brainstem and the granule cells in the cerebellar cortex exhibited light IR. In double immunofluorescence, Shank3 IR occurred at the sublemmal regions in neuronal somata and large dendrites, apposing to synaptophysin-labeled presynaptic terminals. In aged cases, immunolabeled neuronal somata were reduced, with disrupted neuropil labeling seen in the molecular layer of the dentate gyrus in AD cases. In immunoblot, levels of Shank3 protein were positively correlated with that of the postsynaptic density protein 95 (PSD95) among different brain regions. Levels of Shank3, PSD95, and synaptophysin immunoblotted in the prefrontal, precentral, and cerebellar cortical lysates were reduced in the aged and AD relative to youth and adult groups. Taken together, the differential Shank3 expression among brain structures/regions indicates the varied local density of the excitatory synapses. The enriched Shank3 expression in the forebrain subregions appears inconsistent with a role of this protein in the modulation of high cognitive functions. The decline of its expression in aged and AD brains may relate to the degeneration of excitatory synapses.

Dystrophic neurites (DNs) are found in many neurological conditions such as traumatic brain injury and age-related neurodegenerative diseases. In Alzheimer’s disease (AD) specifically, senile plaques containing silver-stained DNs were already described in the original literature defining this disease. These DNs could be both axonal and dendritic in origin, while axonal dystrophy relative to plaque formation has been more extensively studied. Here, we demonstrate an early occurrence of dendritic dystrophy in the hippocampal CA1 and subicular regions in human brains (n = 23) with primary age-related tauopathy (PART), with neurofibrillary tangle (NFT) burden ranging from Braak stages I to III in the absence of cerebral β-amyloid (Aβ) deposition. In Bielschowsky’s silver stain, segmented fusiform swellings on the apical dendrites of hippocampal and subicular pyramidal neurons were observed in all the cases, primarily over the stratum radiatum (s.r.). The numbers of silver-stained neuronal somata and dendritic swellings counted over CA1 to subiculum were positively correlated among the cases. Swollen dendritic processes were also detected in sections immunolabeled for phosphorylated tau (pTau) and sortilin. In aged and AD brains with both Aβ and pTau pathologies, silver- and immunolabeled dystrophic-like dendritic profiles occurred around and within individual neuritic plaques. These findings implicate that dendritic dystrophy can occur among hippocampal pyramidal neurons in human brains with PART. Therefore, as with the case of axonal dystrophy reported in literature, dendritic dystrophy can develop prior to Alzheimer-type plaque and tangle formation in the human brain.